Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Melanoma that developed resistance to anti-PD-1 therapy started responding again after injection of a toll-like receptor 9 (TLR9) agonist directly into the tumor.

Note that examination of untreated melanoma lesions revealed shrinkage in some cases, suggesting an "abscopal" effect, or local treatment that induces a systemic effect.

CHICAGO -- Melanoma that developed resistance to anti-PD-1 therapy started responding again after injection of a toll-like receptor 9 (TLR9) agonist directly into the tumor, a preliminary clinical trial showed.

Overall, 18 of 85 patients regained responsiveness to the PD-1 inhibitor pembrolizumab (Keytruda) after injection with CMP-001. The total response rate included three patients who continued treatment after progression.

Examination of untreated melanoma lesions revealed shrinkage in some cases, suggesting an "abscopal" effect, or local treatment that induces a systemic effect, Mohammed Milhem, MD, of the University of Iowa in Iowa City, reported at the American Association for Cancer Research (AACR) annual meeting.

"The combination of CMP-001 and pembrolizumab appears well tolerated and can produce deep and durable systemic clinical responses," Milhem said during an AACR press briefing. "Results from immunohistochemistry, RNA sequencing, and chemokine analysis are consistent with activation of plasmacytoid dendritic cells by CMP-001 through TLR9 signaling. Enrollment into the expansion phase of this study continues, and clinical investigation in other tumor types is under way."

The phase Ib study involved patients with advanced melanoma that did not respond or developed resistance to anti-PD-1 immunotherapy, which is standard of care for the disease. About half of patients who initially respond to anti-PD-1 therapy subsequently develop resistance to treatment, leaving them with limited options for continued treatment.

Multiple strategies to prevent resistance or restore melanoma's responsiveness to immunotherapy are under investigation.

"Toll-like receptors are found in the innate immune system," said press briefing moderator Suzanne Topalian, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore. "In this case, one of the toll-like receptors, TLR9, is being leveraged therapeutically to provide a strong stimulus for immune responses."

Previous studies showed that tumors with increased expression of interferon are more responsive to anti-PD-1 immunotherapy. The TLR9 signaling pathway has the greatest potential for induction of interferon gene expression, Milhem said of the rationale for developing a TLR9 agonist to restore anti-PD-1 activity in melanoma.

CMP-001 consists of a synthetic immunostimulatory DNA molecule (CpG-A) encased in a nonreplicating virus-like particle that protects the DNA from degradation. The drug stimulates TLR9 activity, which leads to activation of tumor-associated plasmacytoid dendritic cells and induction of an interferon-rich microenvironment and antitumor T-cell activation.

The phase Ib trial consisted of a dose-finding component, followed by an expansion study with the chosen dose and administration schedule. Patients continued to receive pembrolizumab along with CMP-001. Milhem reported results from the dose-finding and expansion phases, the latter of which is ongoing.

The combination of CMP-001 and pembrolizumab led to an overall response rate of 22%, consisting of two complete responses, 13 partial responses, and three additional responses that occurred after initial disease progression. Milhem said 13 of the 18 responding patients continued to receive treatment, and the median duration of response had yet to be reached.

Most responses persisted beyond 6 months and several for more than a year, he added. Responses continued in some patients after treatment ended.

A limitation of CMP-001 is the requirement for an accessible lesion, such as one on the skin surface, a palpable lesion under the skin, or a lymph node. However, investigators detected shrinkage of untreated melanoma lesions in several patients, providing evidence that the treatment has abscopal activity, essentially stimulating a systemic immune response that affects lesions other than those that are directly injected, said Milhem.

Enrollment in the expansion of the phase continues, he added, and clinical investigation of CMP-001 has expanded into other types of tumors.

Given that many patients do not respond to immunotherapy and others develop resistance to the treatment, investigations such as the one described by Milhem have substantial implications for the field of immuno-oncology, said Topalian.

"This trial looks at a very important group of patients -- those who do not respond to anti-PD-1 treatment or who have stable disease but don't make it over the threshold to a complete or partial response," she said. "The question is how can we further activate the immune system to get those patients over that threshold to response?"

In response to a question, Milhem acknowledged that CMP-001 might also have a "priming" effect in patients who discontinued anti-PD-1 treatment because of loss of response. Rechallenging with anti-PD-1 therapy might be feasible in such patients.

The study was supported by Checkmate Pharmaceuticals.

Milhem disclosed no relevant relationships with industry.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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